How to Make Adaptive Dose-Finding Trials Easy for the Clinician

The drive to expedite arriving at the MTD (Maximum Tolerated Dose) in oncology clinical trials could result in many clear benefits: first and foremost, there will be fewer cancer patients in clinical studies receiving too high or too low of a dose of a given investigational product. Beyond that, there will be a need for fewer overall patients, and there will be a greater chance of success moving into Phase II. In fact, there is literature that takes a theoretical approach that indicates 70% of the time, studies (and therefore patients) are missing the best dose.

A more direct route to the MTD not only benefits patients, but the sponsors as well. Moving dose escalation forward faster equals saved time and money. Large companies trying to determine which of their dozens of compounds they should continue to pursue could make cost-effective R&D decisions. For emerging companies, treating patients at ineffective doses appears to indicate their drug is not working; in reality, it could be the dose and not the compound. A new way of thinking (getting phase II data from a phase I study) could secure an additional round of financing.

All of this begs the question: what is holding back getting to the MTD sooner? The real roadblock is acknowledging the difficulty in getting clinicians over the fear of the complexity of creating a new dose escalation model. Many statisticians and clinicians in clinical trials are apprehensive to try new techniques. In this business, the “KISS” (Keep It Simple Stupid) rule has been in full effect for decades. Looking back, regulatory reviews were already long, with agencies trying to figure out the data. The last thing anyone wanted was for the regulators to have to figure out a new analysis as part of the review process. The idea was that it would take longer for a decision to come from a review–and nobody wanted that. These legacy fears remain today.

Implementing a model-based design requires that the statistician is familiar with the method well enough for a successful implementation, and a clinical team that recognizes the benefits, or better, actually asks for a design that offers the benefits. These designs can be implemented in areas other than oncology as well. Rare diseases often have similar challenges as oncology. It can work as long as the development program has as its objective to find the highest dose possible that causes the least harm.

Another key question is: what is the first step in getting started? We need to be careful to not fall into the classic design trap, which is asking if a study can be done with an innovative design. The better approach is to identify which questions need to be answered on the path to approval, then evaluate which designs are the most efficient (in terms of fewest patients exposed, faster timelines, and less cost). Often, an innovative design has the potential to answer more than one question at a time. Seamless designs do exactly that.

The bottom line in all of this is that clinical development programs can be made better without being made more difficult, and that this can be done without trepidation.

Join this webinar to learn about efficiently finding the maximum tolerated dose in oncology drug trials.

Speakers

John Friend, MD, Chief Medical Officer, Cellectar Biosciences, Inc.

Dr. Friend has more than 17 years of global drug development and medical affairs expertise in hematology/oncology as well as a variety of other therapeutic indications. He is currently the Chief Medical Officer of Cellectar Biosciences, leading its research and development, clinical, medical affairs and regulatory affairs divisions.

Prior to this, Dr. Friend has held executive responsibility for clinical research, medical affairs, pharmacovigilance and risk management at various small to large pharmaceutical companies including DRGT, Helsinn Therapeutics, Akros Pharma, Actavis, Alpharma, Hospira and Abbott. He completed his post-graduate residency program in family medicine and subsequently served as Clinical Director and Faculty Attending Physician at Cabarrus Family Medicine Residency Program in North Carolina. He earned his medical degree from UMDNJ-Robert Wood Johnson Medical School (now Rutgers, RWJMS) and received his undergraduate degree in Chemistry from Southern Methodist University.

Message Presenter

Ed Schnipper, MD, Head of Clinical Development, X-37

Dr. Schnipper is a widely recognized expert in innovative design and management of clinical trials, in several indications, particularly in oncology. He has established a reputation for being able to determine quickly and cost-effectively as to whether a drug is safe and effective. Currently the Head of Clinical Development at X-37, Dr. Schnipper has played key roles in drug development from IND to NDA in diverse organizations. Previously holding leadership positions at Hoffmann-LaRoche, Alza, Cellgate, and Novacea, he has been instrumental in securing approvals of drugs such as Roferon A, Vesanoid, Saquinavir, Doxil, Duros Leuprolide, and Concerta. Dr. Schnipper practiced medical oncology in both the academic and private practice settings before beginning his pharmaceutical career with Hoffmann-La Roche. He holds an MD from Georgetown University, and has completed fellowships in hematology at New York University and oncology at Memorial Sloan Kettering Cancer Center.

Message Presenter

Michael Wisniewski, PhD, Vice-President of Biostatistics and Informatics, Atlantic Research Group

Dr. Wisniewski has over 30 years of experience as a statistician in clinical research. He is currently the VP or Biostatistics and Data Informatics at ARG. Previously, he held similar positions at Covance (formerly Chiltern), PPD and GSK where he has built and led international teams of statisticians. He has designed and led projects in many therapeutic areas including oncology, rare diseases, infectious diseases, respiratory, GI, and metabolic diseases. He has worked on several regulatory submissions and has led teams that have worked on others. He has the unique talent of interpreting and communicating complicated statistical information to non-statisticians for study results as well as for strategy and decision-making. Dr. Wisniewski holds a Ph.D. in Statistics from North Carolina State University.

Message Presenter